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33 INTRODUCTION Prolonged fevers always stood as a challenge for physicians in diagnosing and treating them since time immemorial. The term fever of unknown origin (FUO) is used for those prolonged fevers where history, thorough clinical examination, investigations couldn’t help in diagnosing the cause of fever. Going back to year 1930, studying the aetiological causes of fever of unknown origin was first attempted by Alt et al 1 . All those cases with diagnosis at the time of discharge were included in the study. In 1961, Petersdorf and Beeson 2 postulated certain criteria in defining FUO. This definition was used for more than three decades till Durack and Street 3 proposed a revised system for classification of FUO, that is more accountable for endemic and emerging diseases, improved diagnostic technologies, and adverse reactions to new therapeutic interventions. CASE DEFINITION report on 100 cases of fever of unexplained origin and they gave the first case definition for fever of unexplained origin (Table 1). 2 They used three criteria in defining this entity. To exclude all the self-limiting acute febrile illnesses they used three weeks criteria and a temperature above 38.3 o C (101 o F) on several Review Article: Fever of unknown origin (FUO): evolution of case definition, changing aetiological spectrum Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati ABSTRACT Prolonged fever is a common problem faced by clinicians in everyday practise. Since the first description of the entity “fever of unexplained origin” by Petersdorf and Beeson in 1961, the case definition of this entity was further refined with modifications over the last 55 years. Durack and Street proposed noteworthy changes in the definition of “fever of unknown origin (FUO)”. First, they divided FUO into four groups, namely, classic, nosocomial, human “one week hospital study” to “three outpatient visits or three days of in-hospital investigations”. The more recent definition modified the temperature recording of above 38.3 o C (101 o F) on “several occasions” to “at least two occasions” and has listed the minimum essential laboratory testing required for diagnosis. The last five decades have also witnessed a change in the aetiological spectrum of FUO. Infectious diseases like tuberculosis are still common form the west. Inspite of great advances in imaging and laboratory diagnostic methods a significant number of patients with FUO remained undiagnosed. Studies from other parts of the world have shown 9%-78% cases of FUO to remain undiagnosed while studies from India have shown this figure to be 0%-27.4%. Generating reliable epidemiological data regarding the aetiological spectrum of FUO will facilitate development of optimal work-up strategy to establish the aetiological diagnosis and facilitate the specific tests. evolution of case definition, changing aetiological spectrum . J Clin Sci Res 2016;5:33-9

. DOI: http://dx.doi.org/10.15380/ 2277-5706.JCSR.15.082. Corresponding author: Dr D. Prabath Kumar, Associate Professor, Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, India. e-mail: drprabath@yahoo.co.in Online access http://svimstpt.ap.nic.in/jcsr/jan-mar16_files/ra16.pdf DOI: http://dx.doi.org/10.15380/2277-5706.JCSR.15.082 Received: December 12, 2015; Accepted: December 30, 2015. Fever of unknown origin Prabhath Kumar, et al 34 occasions to exclude the cases of habitual hyperthermia. Third criteria included in the definition is uncertainity in the diagnosis after one week of hospital study. They have selected this time interval as it would take that much time for the usual haematological, serological and radiological reports to arrive. In 1991 Durack and Street 3 modified the definition given by Petersdorf and Beeson 2 and referred this entity as fever of unknown origin (FUO). They made two noteworthy changes that included dividing FUO into four groups namely classic, nosocomial, human immuno- deficiency virus (HIV) related and neutropenic FUO. This division is rationale as the classical FUO differs from the rest of the three entities both in the spectrum of underlying disease and the clinical approach. The definition for classic FUO given by them (Table 1) is broader and is closely related to the earlier definition of FUO. The second modification is with regard to the Table 1: Definitions used for defining “fever of unknown origin” ESR = erythrocyte sedimentation rate; CRP = C- reactive protein; FUO = fever of unknown origin Petersdorf and Beeson (1961) 2 Durack and Street (1991) 3 Mulders-Manders et al (2015) 4 Fever of unknown origin Prabhath Kumar, et al Fever of unexplained origin is diagnosed by presence of all of the following i. Fever �38.3 °C (�101°F) on several occasions ii. Duration of fever � 3 we eks iii. No certain diagnosis despite 1 week of inpatient investigations Classified FUO into four categories i. C lassical FUO ii. N osocomial FUO iii. N eutropenic FUO iv. HIV - associated FUO Classical FUO is diagnosed by presence of all of the following i. Fever �38.3°C (�101 °F) on several occasions ii. Duration of fever �3 weeks iii. Failure to reach a diagnosis despite three outpatient visits or three days in the hospital without elucidation of a cause or one week of “intelligent and invasive” ambulatory investigation FUO is define d by presence of all of the following i. Fever �38.3 o C (101 o F) on at least two occasions ii. Illness duration ≥3 weeks iii. Diagnosis that remains uncertain after a thorough history taking, physical examination, and the following obligatory investigations; determination of ESR, CRP level; platelet count, leu c ocyte count total and differential; measurement of

haemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies and rhemutoid factor; protein electrophoresis; urina lysis; blood cultures (n=3); urine culture; chest x - ray; abdominal ultrasonography and tuberculin skin test 35 change in time frame from one week’s hospital study to three outpatient visits or three days of in-hospital investigations. The earlier definitions by Petersdorf and Beeson 2 , Durack and Street 3 (Table 1) had stipulated variable time periods, such as “one week hospital study” 2 , “three outpatient visits or three days of in-hospital stay” 3 for the investigations to be carried out. A new definition of FUO (Table 1) has been proposed recently 4 in which the following modifications were proposed. The term “a temperature recording of above 38.3 o C (101 o F) on “several occasions” has been modified to “at least two occasions”; and instead of stipulating an arbitrary time-period for diagnostic work-up, a set of obligatory investigations 5-7 were included in the definition. EPIDEMIOLOGY Search strategy We carried out an online MEDLINE search using the medical subject heading (MeSH) terms “fever of unknown origin”, “aetiology”, “epidemiology”, “India”. Global scenario With the recent advances in diagnostic aids, true FUO is becoming uncommon. This was supported by a report published in Netherlands 7 , where only 73 cases of FUO were registered between December 2003 and July 2005 at 950 bed academic referral hospital and 2800 bed community hospitals 1,8 . In a geographical area, it is important to know the causes of FUO, its magnitude and pattern, as it is important for early diagnosis, and management. Some studies were conducted from the year 1913-2010 across the world at different countries. Most of them showed infectious diseases to be the underlying cause in which diagnosis has been made after invasive investigation. The results of those studies and the location, number of subjects included in those studies is shown in (Table 2). 1,4-20 Indian scenario Epidemiological trends in the aetiology of FUO are different in developing countries when compared to that in developed countries. Sparse data are available from India regarding the clinical course and outcome (Table 3). 9-14 Studies from India revealed that infectious diseases were the leading cause of FUO, followed by malignancies (Table 3). However, among infectious diseases, tuberculosis comprised the major group in two studies 9,11 done at tertiary care teaching hospitals in east India and one study done at north India 10 . Brucellosis and enteric fever were found to be the most common among infectious diseases group in studies done at tertiary care teaching hospital, Srinagar, Kashmir 13 and at a teaching hospital in central India. 12 CHANGING TRENDS IN THE AETIOLOGY In the year

1930 a study on fever of unknown origin was published. 1 Irrespective of the duration of fever all those patients admitted at Peter Bent Brigham hospital, Boston where a single diagnosis could not be arrived after clinical examination and bacteriological examination and in which fever did not resolve at the time of discharge were included in this study 1 . Each such case was seen by atleast two physicians before categorizing the case into “fever of unknown origin”. It showed that in only 11% of cases, infections were found to be the aetiological cause and about 78% of cases remained undiagnosed. This could probably be explained by the unavailability of diagnostic aid at that period. Since the time of the classic paper by Petersdorf and Beeson, 2 several studies 2,5,8,15 that were carried out showed infections to be the major cause of FUO ranging from 20% to 80% and among non-infectious causes inflammatory diseases stood second ranging from 1% to 31% followed by malignancies ranging from 8% to 13%. Fever of unknown origin Prabhath Kumar, et al 36 Stud y Year of publication Period of study Place o f study Population studied Study design No. of cases Aetiological cause (%) Infections Neoplasms Inflammatory diseases Miscelleneous No diagnosis Jung 12 1999 1993 Wardha Adults P 233 46.4 9 20.1 0 .5 24 Handa 10 1996 1996 New Delhi Adults P 121 43.8 8.2 15.7 13.3 19 Kejariwal 11 2001 1998 - 01 Kolkata Adults P 100 53 17 11 05 14 Bandyopadhyay 9 2011 2008 - 09 Kolkata Adults P 164 54.8 22 7.4 3.6 12.2 Shantaram 14 2013 ND Hyderabad Adults ND 100 60 10 24 6 0 Mir 13 2014 2010 - 12 Srinagar Adults P 91 43.9 12.1 12.1 4.5 27.4 Stud y Year of publication Period of study Population studied Place of study Study design No. of cases Aetiological cause (%) Infections Neoplasms Inflammatoryd iseases Miscellaneous No diagnosis Petersdorf 2 1961 1952 - 59 Adul ts Seattle P 100 36 19 17 21 7 Knockaert 8 1994 1980 - 89 Elderly Belgium ND 47 25 12 31 20 12 Miller 15 1996 1989 - 93 AIDS London R 79 80 8 1 2 9 De Kleijn 5 1997 1992 - 94 Adults Netherlands P 167 26 13 24 7 30 Vanderschueren 16 2003 1990 - 99 Adults Belgium P 290 20 10 24 13 34 Tabak 18 2003 1984 - 01 Adults Turkey R 117 34 19 29 4 14 Saltoglu 17 2004 1994 - 02 Adults Turkey P 87 59 14 18 2 7 Ergonul 19 2005 1993 - 99 Adults Turkey P 80 52 18 16 3 11 Chin 20 2006 2001 - 02 Adults Taiwan P 94 57 9 7 9 18 Zenone 21 200 6 1999 - 05 Adults France P 144 23 10 26 15 26 Bleeker - Rovers 7 2007 2003 - 05 Adults Netherlands P 73 16 7

22 4 51 Colpan 22 2007 2001 - 04 Adults Turkey P 71 45 14 27 6 9 Mansueto 23 2008 1991 - 02 Adults Italy R 91 32 14 12 10 32 Hu 24 2008 2002 - 03 Adults Chi na R 142 36 13 32 05 14 Kucukardali 25 2008 2003 - 04 Adults Turkey P 154 34 14 31 05 16 Efstathiou 26 2010 2001 - 07 Adults Greece P 112 30 11 33 05 21 Ali - Eldin 27 2011 2009 - 10 Adults Egypt P 93 42 30 15 0 12 Naito 28 2013 2011 Adults Japan R 121 23.1 10.7 30.6 12.4 23.1 Table 2: Comparison of some of the studies on fever of unknown origin from other parts of the world P = prospective; R = retrospective; ND = not described; AIDS = acquired immunodeficiency syndrome Table 3: Comparison of some of the published studies on fever of unknown origin from India P = prospective; R= retrospective Fever of unknown origin Prabhath Kumar, et al 37 In earlier studies aetiological causes of FUO included fewer cases with connective tissue disease. As of now more cases of connective tissue disease (CTD) are being diagnosed due to increased awareness regarding these cases and their numbers as causes of PUO are declining. Extra-pulmonary tuberculosis (EPTB), solid tumours, and abdominal abscesses are emerging as less frequent causes of FUO presently in developed countries due to early localization of these lesions by radiographic imaging. Image guided biopsies help in diagnosis . Infective endocarditis, which used to be a frequent cause of FUO, has become less common with improved techniques for the isolation of organisms. Figure1A: showing Distribution of aetiological causes of FUO from some of the published studies from other parts of world published since 2005; FUO = fever of unknown origin Source: references 7,19-28 Figure 1B: Distribution of aetiological causes of FUO from some of the published studies from India FUO = fever of unknown origin Source: references 9-14 Fever of unknown origin Prabhath Kumar, et al 38 From the year 2000-2010 7,16-26 there has been a decrease in the incidence of infections ranging from 16%-57%, this is in parallel to slight increase in the proportion of cases diagnosed to have inflammatory diseases. This change could be both due to the increasing awareness on inflammatory diseases as well as advances in nuclear scans helping in localising the active focus responsible for fever. Only few studies 9-14 were conducted in India to comment on the time trends in aetiological causes of FUO. Available data between the period 1999-2014 showed infectious diseases were the leading cause of FUO ranging from 43.8% to 60%, followed by malignancies ranging from 9% to 22% and inflammatory disease ranging from 7.4% to 24%. The results were similar to the results obtained in other parts of the world during that period. This shows the equal distribution of the disease load across

the globe. Inspite of the spectacular advances in imaging and laboratory diagnostic methods, even today, a substantial number of patients with FUO remain undiagnosed (Tables 2 and 3; Figures 1A and 1 B). In studies from India (Table 3) 0%-27.4% of patients remained undiagnosed, while in the studies from other parts of the world, this figure ranged from 9%-78%. Whether these variations merely reflect the changes in the range and availability of diagnostic investigations over time and variations in the diagnostic protocol followed at different centres or, reflect hitherto unknown causes for FUO needs further study. This calls for the need for further research in this area. Data regarding the commonly encountered aetiological causes of FUO in a given clinical setting and their changing trends will facilitate a focussed diagnostic work-up and an optimal strategy to arrive at the aetiological diagnosis so that appropriate specific treatment can be instituted. REFERENCES 1. Alt H, Barker M. Fever of Unknown Origin. JAMA 1930;94:1457-61. 2. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961;40:1-30. 3. Durack DT, Street AC. Fever of unknown origin - reexamined and redefined. Curr Clin Trop Infect Dis 1991;11:35-51. 4. Mulders-Manders C, Simon A, Bleeker-Rovers C. Fever of unknown origin. Clin Med 2015;15:280-4. 5. de Kleijn EM, Vandenbroucke JP, van der Meer JW. Fever of unknown origin (FUO). I A. prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group. Medicine (Baltimore) 1997;76:392-400. 6. de Kleijn EM, van Lier HJ, van der Meer JW. Fever of unknown origin (FUO). II. Diagnostic procedures in a prospective multicenter study of 167 patients. The Netherlands FUO Study Group. Medicine (Baltimore) 1997;76:401-14. 7. Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, Mudde AH, Dofferhoff TSM, Richter C, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore) 2007;86:26-38. 8. Knockaert DC, Mortelmans LA, De Roo MC, Bobbaers HJ. Clinical value of gallium-67 scintigraphy in evaluation of fever of unknown origin. Clin Infect Dis Off Publ Infect Dis Soc Am 1994;18:601-5. 9. Bandyopadhyay D, Bandyopadhyay R, Paul R, Roy D. Etiological study of Fever of unknown origin in patients admitted to medicine ward of a teaching hospital of eastern India. J Glob Infect Dis 2011;3:329-33. 10. Handa R, Singh S, Singh N, Wali JP. Fever of unknown origin: a prospective study. Trop Doct 1996;26:169-70. 11. Kejariwal D, Sarkar N, Chakraborti SK, Agarwal V, Roy S. Pyrexia of unknown origin: a prospective study of 100 cases. J Postgrad Med 2001;47:104-7. 12. Jung A, Singh MM, Jajoo U. Unexplained fever- analysis of 233 cases in a referral hospital. Indian J Med Sci 1999;53:535-44. Fever of unknown origin Prabhath Kumar, et al 39 13. Mir T, Nabi Dhobi G, Nabi Koul A, Sa

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